15-50205321-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003645.4(SLC27A2):c.930G>T(p.Gln310His) variant causes a missense change. The variant allele was found at a frequency of 0.0000845 in 1,609,896 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000082 (1 hom.)
• Consequence: SLC27A2 NM_003645.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.50

Genes affected

SLC27A2 (HGNC:10996): (solute carrier family 27 member 2) The protein encoded by this gene is an isozyme of long-chain fatty-acid-coenzyme A ligase family. Although differing in substrate specificity, subcellular localization, and tissue distribution, all isozymes of this family convert free long-chain fatty acids into fatty acyl-CoA esters, and thereby play a key role in lipid biosynthesis and fatty acid degradation. This isozyme activates long-chain, branched-chain and very-long-chain fatty acids containing 22 or more carbons to their CoA derivatives. It is expressed primarily in liver and kidney, and is present in both endoplasmic reticulum and peroxisomes, but not in mitochondria. Its decreased peroxisomal enzyme activity is in part responsible for the biochemical pathology in X-linked adrenoleukodystrophy. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.761

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC27A2	NM_003645.4	c.930G>T	p.Gln310His	missense_variant	4/10	ENST00000267842.10
SLC27A2	NM_001159629.2	c.771G>T	p.Gln257His	missense_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC27A2	ENST00000267842.10	c.930G>T	p.Gln310His	missense_variant	4/10	1	NM_003645.4	P1
SLC27A2	ENST00000380902.8	c.771G>T	p.Gln257His	missense_variant	3/9	1
SLC27A2	ENST00000544960.1	c.225G>T	p.Gln75His	missense_variant	5/11	2
SLC27A2	ENST00000559938.1			upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152070 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000600 AC: 15 AN: 250118 Hom.: 0 AF XY: 0.0000592 AC XY: 8 AN XY: 135168

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000295

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000816 AC: 119 AN: 1457826 Hom.: 1 Cov.: 30 AF XY: 0.0000758 AC XY: 55 AN XY: 725224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000103

Gnomad4 OTH exome AF: 0.0000499

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152070 Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 10 AN XY: 74252

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000986 Hom.: 0

Bravo AF: 0.0000680

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000741 AC: 9

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 09, 2023

The c.930G>T (p.Q310H) alteration is located in exon 4 (coding exon 4) of the SLC27A2 gene. This alteration results from a G to T substitution at nucleotide position 930, causing the glutamine (Q) at amino acid position 310 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Uncertain	-0.050
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.36	T;.;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T;D;D
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.76	D;D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.7	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-4.5	D;D;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.018	D;D;T
Sift4G	Uncertain	0.031	D;T;T
Polyphen		0.92	P;.;.
Vest4		0.86
MutPred		0.80		Gain of sheet (P = 0.0827);.;.;
MVP		0.66
MPC		0.35
ClinPred		0.69	D
GERP RS		5.3
Varity_R		0.51
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs368796882; hg19: chr15-50497518;